Nrf2 transcriptionally activates the mafG gene through an antioxidant response element
Nrf2 transcriptionally activates the mafG gene through an antioxidant response element
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DOI：
10.1074/jbc.m411451200
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发表时间：
2005-02-11
影响因子：
4.8
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Katsuoka, F;Motohashi, L;Yamamoto, M
Nrf 2在氧化应激时在细胞核中积累，与小Maf蛋白异源二聚化，并通过抗氧化反应元件（战神）激活应激靶基因的转录。我们发现马来酸二乙酯（DEM），一个众所周知的Nrf 2激活剂，诱导一个小Maf基因，mafG。为了阐明MafG在氧化应激反应中可能发挥的作用，我们研究了小鼠mafG基因的转录调控。MatG利用三个独立的第一外显子，每个外显子与第二和第三编码外显子拼接。在小maf基因中，maf G显示出对DEM的最强响应，并且在三个前外显子中，近端第一外显子（Ic）的诱导倍数最高。重要的是，一个ARE（Ic-ARE）在人和小鼠mafG基因的启动子侧翼外显子Ic中是保守的。Nrf 2/MafG异源二聚体结合Ic-ARE并激活转录，而DEM未能激活nrf 2-null突变细胞中的mafG。染色质免疫沉淀进一步揭示了Nrf 2和小Maf蛋白在体内与le-ARE结合。这些结果表明，mafG本身是一个ARE依赖的基因，由Nrf 2/小Maf异源二聚体调节，并建议mafG转录调节的自动调节反馈途径的存在。
Nrf2 accumulates in nuclei upon exposure to oxidative stress, Heterodimerizes with a small Maf protein, and activates the transcription of stress target genes through antioxidant response elements (AREs). We found that diethyl maleate (DEM), a well known activator of Nrf2, induces one of the small Maf genes, mafG. To elucidate roles MafG might play in the oxidative stress response, we examined transcriptional regulation of the mouse mafG gene. MatG utilizes three independent first exons that are each spliced to second and third coding exons. Among the small maf genes, mafG showed the strongest response to DEM, and of the three first exons, the highest -fold induction was seen with the proximal first exon (Ic). Importantly, one ARE (Ic-ARE) is conserved in the promoter flanking exon Ic of the human and mouse mafG genes. The Nrf2/MafG heterodimer bound the Ic-ARE and activated transcription, whereas DEM failed to activate mafG in nrf2-null mutant cells. Chromatin immunoprecipitation further revealed that both Nrf2 and small Maf proteins associate with the le-ARE in vivo. These results demonstrate that mafG is itself an ARE-dependent gene that is regulated by an Nrf2/small Maf heterodimer and suggest the presence of an autoregulatory feedback pathway for mafG transcriptional regulation.